This proposal describes a 4 year training program for the development of my academic career in Pediatric Hematology, Oncology, and Stem Cell Transplantation. I have completed formal residency training in General Pediatrics and subspecialty fellowship training in Pediatric Hematology and Oncology at The Children's Hospital of Philadelphia (CHOP). I now seek to expand my scientific skills to enable my transition to becoming a successful independent investigator. My research program will promote discoveries in stem cell niche biology, mechanisms of donor stem cell engraftment following transplantation, and pathogenic mechanisms of graft failure in models of inherited bone marrow failure syndromes. Dr. Monica Bessler, M.D., Ph.D. and Dr. Edwin Horwitz, M.D., Ph.D., will mentor my scientific development. Dr. Bessler, Director of the Comprehensive Bone Marrow Failure Center at CHOP and the University of Pennsylvania (UPENN), is an international leader in research dedicated to the diagnosis and pathogenesis of bone marrow failure conditions, and has successfully mentored numerous trainees who have become leaders in academic medicine. Dr. Horwitz, Associate Professor of Pediatrics at CHOP and UPENN, is an international leader in the fields of bone marrow mesenchymal cell biology and cellular therapy, and has a growing record of fostering trainee career development. My mentorship team provides an ideal combined expertise and experience to facilitate my successful completion of this research program. I have also organized a Scientific Advisory Committee of highly regarded investigators consisting of Drs. Mortimer Poncz, M.D., Stephan Grupp, M.D. Ph.D., and Philip Mason, Ph.D., whose combined expertise in megakaryocyte biology, cellular therapy research, bone marrow failure models, and career development will provide invaluable contributions to my future success. Additionally, I have formed collaborative agreements with Dr. D. Wade Clapp from the University of Indiana, and Dr. Johanna Rommens from the University of Toronto, to provide me with specific mouse models of bone marrow failure critical for the success of these studies. The research builds upon my previous investigations demonstrating that reorganization and expansion of the osteoblastic hematopoietic stem cell (HSC) niche in response to transplant myeloablative conditioning regimens are essential for efficient HSC engraftment. Our proposed experiments will utilize transgenic mouse models and therapeutic interventions designed to disrupt or enhance this niche reorganization, and will identify whether these alterations influence the capacity of the niche to engraft donor HSC. The specific aims include: 1) Identifying synergistic and essential mechanisms by which PDGF-BB, IGF-1, and megakaryocyte migration to the osteoblastic niche influence niche expansion and HSC engraftment, 2) Investigating whether models of inherited bone marrow failure demonstrate intrinsic deficits in niche function resulting in poor donor HSC engraftment, and 3) Determining whether PDGF-BB administration or megakaryocyte infusion can enhance niche expansion and niche capacity to engraft donor HSC. Our completion of these proposed studies will have profound translational implications in 1) discovering the cellular and molecular mechanisms that drive successful stem cell engraftment at the niche, 2) determining how niche dysfunction may lead to graft failure, and 3) identifying rationally targeted therapies to enhance successful donor engraftment rates following clinical stem cell transplantation. My prior research efforts were focused on the hematopoietic stem cell niche. Training through this K08 award will expand both my scientific training to discover roles of the hematopoietic niche in bone marrow failure syndromes, while at the same time facilitating my development of clinical career skills in the care of patients affected by thes disorders. These two new directions will involve mentoring and training in the scientific areas related to inherited and acquired bone marrow failure, and will be the primary focus of my interactions with Dr. Bessler as senior mentor. The numerous interdisciplinary centers, collaborative investigator affinity groups, and unique didactic training opportunities at CHOP and UPENN provide an exceptional scientific environment for the training of physician-scientists. I plan to take full advantage of the diverse intellectual areas of expertise and academic experiences of my outstanding mentors, advisory committee members, and collaborators to successfully develop my unique and independent program of scientific investigation. Given the exceptional opportunities and training afforded by this prestigious K08 program, I will devote my career to making high impact scientific contributions to the field of hematology and to training future generations of physician-scientists.